The cell surface receptor, low-density lipoprotein receptor-related protein 5 (LRP5) is a key regulator of bone mass and strength. LRP5 loss-of-function mutations cause severely low bone mass, while specific missense mutations cause extremely high bone mass (HBM). Our research program has generated data indicating that LRP5 functions within bone as part of the mechanotransduction pathway. The research proposed in this application is intended to pinpoint precisely which cell type(s) in bone require LRP5 for mechanotransduction, to determine when and how much Lrp5 HBM alleles can improve mechanotransduction and other bone properties when the HBM alleles are activated after birth, to uncover which potential up-stream modulators of the LRP5 - SOST axis are required during mechanotransduction, and to learn how the cells that experience altered LRP5 activity in response to changes in mechanical load send signals to effector cells at bone surfaces to either produce new bone or resorb unneeded bone. We will use our recently developed mouse models (e.g., conditionally activated Lrp5 HBM alleles) and mouse models recently developed by other investigators, in order to answer the questions posed in our four Aims. Our goal is to understand the where's, when's, which's, and how's of LRP5 action in mechanotransduction, which can ultimately lead to the discovery of new therapies that improve human bone health. PUBLIC HEALTH RELEVANCE: This research aims to understand the pathway in which the cell surface receptor LRP5 functions to regulate bone mass and bone strength in humans. Genetic absence of LRP5 causes very low bone mass, while other mutations in this protein can cause very high bone mass. We will study mice that express different forms of LRP5 to determine where, when, and how it participates in mechanotransduction, and consequently, affects bone mass and fracture susceptibility.